Sleep disruption due to nocturnal heartburn: a review of the evidence and clinical implications

Nocturnal heartburn (NHB) is a symptom that affects up to 25% of the general population and has been shown to cause sleep disruption that adversely affects quality of life and psychomotor performance. Few studies have evaluated the association between occasional NHB and sleep disturbances; therefore, this connection may be underappreciated and left untreated by the primary care provider and patient, with potentially significant negative clinical consequences and effects on quality of life. This review sought to describe what is currently known about the interplay between occasional NHB and sleep disruption, and identify whether acid suppression therapy can improve symptoms of occasional NHB and associated sleep disruptions. The pathophysiology of heartburn-induced sleep disruption appears to follow a bidirectional cycle due to the normal physiologic changes that occur in the upper gastrointestinal tract during sleep and due to the potential for heartburn symptoms to cause sleep arousal. The majority of the identified studies suggested that pharmacologic interventions for acid reduction, including proton pump inhibitors or histamine type-2 receptor antagonists (H2RAs), improved objective and/or subjective sleep outcomes among individuals with gastroesophageal reflux disease (GERD) and NHB. Several studies specific to famotidine demonstrated that treatment with 10 mg or 20 mg reduced nighttime awakenings due to NHB. In conclusion, NHB symptoms can cause sleep dysfunction that can have a profound adverse downstream effect on quality of life, next-day functioning, and health-related outcomes. The current approach to managing occasional NHB is similar to that associated with GERD, highlighting the need for studies specific to the occasional heartburn population. Health care providers should investigate NHB as one of the potential causes of sleep complaints, and patients with heartburn should be questioned about sleep quality, recalled arousals, next-day vitality, early fatigue, and next-day functioning

Glucuronidation of PhIP and N-OH-PhIP by UDP-glucuronosyltransferase 1A10

The UDP-glucuronosyltransferase (UGT) 1A10 is an extra-hepatic enzyme that plays an important role in the glucuronidation of a variety of endogenous and exogenous substances and is expressed throughout the aerodigestive and digestive tracts. Two classes of carcinogens that target the colon, heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons, are known to be detoxified by the UGT family of enzymes. Recently, our laboratory demonstrated that UGT1A10 has considerably more activity against polycyclic aromatic hydrocarbons in vitro than any other UGT family member. In this study, we focused on the glucuronidation of the HCA, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and its bioactivated metabolite, N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP). We demonstrated that UGT1A10 exhibited a significantly higher glucuronidation rate against PhIP and N-OH-PhIP than any other UGT family member in vitro using whole-cell homogenates of HEK293 cells over-expressing individual UGTs. Kinetic analysis revealed a 9- and 22-fold higher level of activity for UGT1A10 homogenates as compared with the next most active UGT, UGT1A1, against N-OH-PhIP as determined by maximum rate/apparent Michaelis constant (V max/K M) at the N3 and N 2 positions, respectively. The polymorphic UGT1A10139Lys variant exhibited a 2- to 16-fold decrease in glucuronidation activity against PhIP and N-OH-PhIP, as compared with the wild-type UGT1A10139Glu isoform. These data suggest that UGT1A10 is the most active UGT against PhIP and N-OH-PhIP and that UGT1A10 may play an important role in susceptibility to HCA-induced colon cancer

Characterization of UDP-glucuronosyltransferase 2A1 (UGT2A1) variants and their potential role in tobacco carcinogenesis

UDP-glucuronosyltransferases (UGTs) play an important role in the metabolism and excretion of various endogenous and xenobiotic compounds, including carcinogens and chemotherapeutic agents. The goal of the present study was to examine UGT2A1 expression in human tissues, determine its glucuronidation activity against tobacco carcinogens, and assess the potential functional role of UGT2A1 missense single nucleotide polymorphisms on UGT2A1 enzyme activity. As determined by reverse-transcription polymerase chain reaction, UGT2A1 was expressed in aerodigestive tract tissues including trachea, larynx and tonsil, and was also expressed in lung and colon; no expression was observed in breast, whole brain, pancreas, prostate, kidney, liver or esophagus. Real-time PCR suggested that UGT2A1 exhibited highest expression in the lung, followed by trachea > tonsil > larynx > colon > olfactory tissue. Cell homogenates prepared from wild-type UGT2A1 75Lys308Gly -over-expressing HEK293 cells showed significant glucuronidation activity, as observed by reverse-phase UPLC, against a variety of polycyclic aromatic hydrocarbons (PAHs) including, 1-hydroxy-benzo(a)pyrene, benzo(a)pyrene-7,8-diol, and 5-methylchrysene-1,2-diol. No activity was observed in UGT2A1-over-expressing cell homogenate against substrates that form N -glucuronides, such as NNAL, nicotine, or N -OH-PhIP. A significant (p<0.05) ~25% decrease in glucuronidation activity (V max /K M ) was observed against all PAH substrates for the UGT2A1 75Arg308Gly variant as compared to homogenates from wild-type UGT2A1 75Lys308Gly ; no activity was observed for cell homogenates over-expressing the UGT2A1 75Lys308Arg variant for all substrates tested. These data suggest that UGT2A1 is an important detoxification enzyme in the metabolism of PAHs within target tissues for tobacco carcinogens, and functional polymorphisms in UGT2A1 may play a role in tobacco-related cancer risk

Functional Significance of UDP-Glucuronosyltransferase Variants in the Metabolism of Active Tamoxifen Metabolites

Tamoxifen (TAM) is a selective estrogen receptor modulator widely used in the prevention and treatment of breast cancer. A major mode of metabolism of the major active metabolites of TAM, 4-OH-TAM and endoxifen, is by glucuronidation via the UDP-glucuronosyltransferase (UGT) family of enzymes. To examine whether polymorphisms in the UGT enzymes responsible for the glucuronidation of active TAM metabolites play an important role in inter-individual differences in TAM metabolism, cell lines over-expressing wild-type or variant UGTs were examined for their activities against TAM metabolites in vitro. For variants of active extra-hepatic UGTs, the UGT1A8(173Ala/277Tyr) variant exhibited no detectable glucuronidation activity against the trans isomers of either 4-OH-TAM or endoxifen. No difference in TAM glucuronidating activity was observed for the UGT1A8(173Gly/277Cys) or UGT1A10(139Lys) variants as compared to their wild-type counterparts. For active hepatic UGTs, the UGT2B7(268Tyr) variant exhibited significant (p<0.01) 2- and 5-fold decreases in activity against the trans isomers of 4-OH-TAM and endoxifen, respectively, as compared to wild-type UGT2B7(268His). In studies of 111 human liver microsomal specimens, the rate of O-glucuronidation against trans-4-OH-TAM and trans-endoxifen was 28% (p<0.001) and 27% (p=0.002) lower, respectively, in individuals homozygous for the UGT2B7 Tyr268Tyr genotype as compared to subjects with the UGT2B7 His268His genotype, with a significant (p<0.01) trend of decreasing activity against both substrates with increasing numbers of the UGT2B7(268His) allele. These results suggest that functional polymorphisms in TAM-metabolizing UGTs, including UGT2B7 and potentially UGT1A8, may be important in inter-individual variability in TAM metabolism and response to TAM therapy